Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids

ABSTRACT

Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids and the pharmaceutically acceptable salts thereof are produced by coupling a suitably substituted 1,2,3,4-tetrahydroisoquinoline with a suitably substituted amino acid and when desired hydrolyzing or removing protecting groups of the resulting product. The compounds of the invention, their salts and pharmaceutical compositions thereof are useful as antihypertensive agents.

This is a continuation-in-part of copending United States Patentapplication U.S. Ser. No. 193,767, filed Oct. 3, 1980, now abandoned.

SUMMARY AND DETAILED DESCRIPTION

The invention relates to substituted acyl derivatives of1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid compounds having theformula ##STR1## where R is hydrogen, lower alkyl or aralkyl; R₁ ishydrogen, lower alkyl, or benzyl; R₂ is hydrogen or lower alkyl, and Aris phenyl or phenyl substituted with 1 or 2 substituents selected fromthe group consisting of fluorine, chlorine, bromine, lower alkyl, loweralkoxy, hydroxy or amino; X and Y are independently hydrogen, loweralkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, hydroxy, or X and Y together are methylenedioxy; m is 0to 3; and the pharmaceutically acceptable acid salts thereof.

Preferred compounds of the invention are acylated1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids having the formula##STR2## where R₁ is hydrogen or lower alkyl containing 1 to 3 carbonatoms, R₂ is hydrogen or lower alkyl containing 1 to 3 carbon atoms andAr is phenyl, and phenyl substituted in the para position by fluorine,chlorine, bromine, methyl, hydroxy, methoxy or amino, X and Y are asdefined above; and pharmaceutically acceptable acid salts thereof.

Further preferred compounds of the invention are acylated1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids having the formula##STR3## where R₂ is hydrogen or lower alkyl containing 1 to 3 carbonatoms X and Y are independently hydrogen or lower alkoxy andpharmaceutically acceptable acid salts thereof; and specifically thecompounds designated2-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid;2-[2-[[(1-ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid;2-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid; 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid; and pharmaceutically acceptable acid salts thereof.

The terms "lower alkyl" and "lower alkoxy" are intended to mean astraight or branched alkyl group of from one to four carbon atoms.

The compounds of the invention of formula I have asymmetric carbon atomsindicated by asterisks. The 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid used in this invention has the L (S) configuration. Thisconfiguration has been shown to be required for biological activity, andthus active compounds of the invention are derived from either L(-) orDL-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids.

Optical and diastereo isomers arising from the chirality at the centersmarked with an asterisk in formula I and racemates and mixtures thereofare within the scope of this invention. The S configuration at thesecenters is preferred.

The compounds of the invention may exist in anhydrous form as well as insolvated, including hydrated forms. In general, the hydrated forms andthe solvated forms with pharmaceutically acceptable solvents areequivalent to the anhydrous or unsolvated form for the purposes of theinvention.

The compounds of the invention of formula I may be prepared from1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid by first protecting thecarboxylic acid group, preferably as an ester, e.g., with a lower alkyl,benzyl or trimethylsilyl group. The protected carboxylic acid compoundis coupled to an N-protected amino acid, e.g., glycine or L-alanine,protected on nitrogen with t-butyloxycarbonyl or benzyloxycarbonyl. Thecoupling is carried out by any of a variety of standard peptide couplingtechniques as disclosed, for example, in "The Peptides. Analysis,Synthesis, Biology, Vol. 1 Major Methods of Peptide Bond Formation, PartA", ed. E. Gross, J. Meierhofer, Academic Press N.Y. (1979). Anespecially useful method involves the use of a dehydrating agent, suchas dicyclohexylcarbodiimide alone or in the presence of reagents formingreactive esters, e.g., 1-hydroxybenztriazole, in suitable aproticsolvents such as dimethylformamide, acetonitrile, tetrahydrofuran orchlorinated hydrocarbons. This gives the intermediate(N-protected-2-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid esters. These may then be either partially or totally deblockeddepending on the protecting groups chosen, using anhydrous acids, e.g.,hydrochloric acid in acetic acid or trifluoroacetic acid in methylenechloride, or hydrogen gas and a catalyst to give the intermediatedipeptide either in free form or protected as an ester.

The compounds of the invention of formula I may then be prepared byreacting the intermediate dipeptide or its ester derivative withα-keto-4-substituted phenylbutyric acid or its lower alkyl esterderivatives under dehydrating and reducing conditions. Preferreddehydrating agents include molecular seives in aprotic solvents andpreferred reducing agents include sodium cyanoborohydride or hydrogengas with a catalyst.

Alternatively, the dipeptide or its ester derivative may be reacted withan α-halo-4-substituted phenylbutyric acid or its ester in the presenceof a suitable basic reagent, such as triethylamine or alkali carbonatesor bicarbonates, in a solvent, to give the compounds of the invention offormula I. Ester protected products may be hydrolyzed under basic oracidic reaction conditions to free acid derivatives, or, in the case ofbenzyl esters, catalytic hydrogenolysis may be preferred.

Alternately, compounds of the invention of formula I may be prepared ina different manner. This consists of applying either of the two methodsdescribed above for the attachment of the 2-(4-phenylbutyric acid)moiety to the protected dipeptide, first to glycine or L-alanine, whichmay be protected as an ester, to give N-[2-(4-phenylbutyricacid)]-substituted glycine or L-alanine derivative.

After selective deblocking of the acid moiety on the glycine or alanineportion of the product, the resulting monoacid may be coupled, eitherdirectly or subsequent to suitable blocking of the amino group, viastandard peptide coupling procedures to the1,2,3,4-tetrahydro-3-isoquinoline carboxylate, protected as an ester.Selective or complete removal of the ester groups and any amineprotecting groups yield the compounds of formula I.

The products are obtained typically as a mixture of diastereoisomerswhich can be separated by standard methods of fractional crystallizationor chromatography.

The compounds of this invention form acid salts with various inorganicand organic acids which are also within the scope of the invention. Thepharmaceutically acceptable acid addition salts of the compounds of thepresent invention may be prepared by conventional reactions by reactingthe free amino acid or amino ester form of the product with one or moreequivalents of the appropriate acid providing the desired anion in asolvent or medium in which the salt is insoluble, or in water andremoving the water by freeze drying. The salts of strong acids arepreferred. As exemplary, but not limiting, of pharmaceuticallyacceptable acid salts are the salts of hydrochloric, hydrobromic,sulfuric, nitric, acetic, fumeric, malic, maleic and citric acids.

The action of the enzyme renin on angiotensinogen, a pseudoglobulin inblood plasma, produces the decapeptide angiotensin I. Angiotensin I isconverted by angiotensin converting enzyme (ACE) to the octapeptideangiotensin II. The latter is an active pressor substance which has beenimplicated as the causative agent in various forms of hypertension invarious mammalian species, e.g., rats and dogs. The compounds of thisinvention intervene in the renin->angiotensin I->angiotensin II sequenceby inhibiting angiotensin I converting enzyme and reducing oreliminating the formation of the pressor substance angiotensin II, andtherefore are useful in reducing or relieving hypertension. Thus by theadministration of a composition containing one or a combination ofcompounds of formula I or pharmaceutically acceptable salts thereof,hypertension in the species of mammal suffering therefrom is alleviated.A single dose, or preferably two to four divided daily doses, providedon a basis of about 0.1 to 100 mg per kilogram per day, preferably about1 to 50 mg per kilogram per day, is appropriate to reduce bloodpressure. The substance is preferably administered orally, butparenteral routes such as subcutaneusly, intramuscularly, intravenouslyor intraperitonealy can also be employed.

In vitro ACE Assay: Angiotensin converting enzyme (ACE) inhibitoryactivity was determined by assaying guinea pig serum ACE in the presenceand absence of the test compound. ACE from guinea pig serum and the testcompounds were preincubated for 10 minutes before the addition of thelabelled substrate ³ H-hippuryl-glycyl-glycine. After a 60 minuteincubation of 37° C. the reaction was stopped by the addition of 0.1 NHCl. ACE cleaves the hippuryl-glycyl bond to form the dipeptideglycyl-glycine and ³ H-hippuric acid. The ³ H-hippuric acid was thenextracted with ethyl acetate and the ACE activity of a given samplecalculated as the amount of ³ H-hippuric acid generated.

                  TABLE                                                           ______________________________________                                        Acyl Derivatives of                                                           1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids                             (S,S,S configuration) and their In-Vitro                                      Angiotensin-Converting Enzyme Inhibitory Activity                              ##STR4##                                                                                               Optical   ACE I Activity                                                      Rotation  (in vitro)                                R     R.sub.2                                                                             X       Y     [a].sub.D.sup.23                                                                        IC.sub.50 Molar Conc.                     ______________________________________                                        H     Et    H       H     +10.9°                                                                           8.3 × 10.sup.-9                                               (1.0% EtOH).sup.+                                   H     Et    OCH.sub.3                                                                             OCH.sub.3                                                                           +31.6°                                                                           5.6 × 10.sup.-9                                               (1.0% EtOH).sup.+                                   H     H     H       H     +14.5°                                                                           2.8 × 10.sup.-9                                               (1.0% MeOH).sup.+                                   H     H     OCH.sub.3                                                                             OCH.sub.3                                                                           +37.8°                                                                           3.4 × 10.sup.-9                                               (1.0% MeOH).sup.+                                   PhCH.sub.2                                                                          Et    H       H     -11.7°                                                                           2.0 × 10.sup.-6                                               (1.0% MeOH).sup.#                                   t-Bu  Et    H       H     +6.4°                                                                            3.2 × 10.sup.-6                                               (2.0% MeOH).sup.#                                   PhCH.sub.2                                                                          Et    OCH.sub.3                                                                             OCH.sub.3                                                                           +3.4°                                                                            3.0 × 10.sup.-7                                               (1.0% EtOH).sup.#                                   ______________________________________                                         .sup.+ Hydrochloride Salt                                                     .sup.# Maleate Salt                                                      

The compounds of the invention can be utilized to achieve the reductionof blood pressure by formulating in compositions such as tablets,capsules or elixirs for oral administration or in sterile solutions orsuspensions for parenteral administration. About 10 to 500 mg of acompound or mixture of compounds of formula I or physiologicallyacceptable salt thereof is compounded with a physiologically acceptablevehicle, carrier, excipient binder, preservative, stabilizer, flavor,etc., in a unit dosage form as called for by accepted pharmaceuticalpractice. The amount of active substance in these compositions orpreparations is such that a suitable dosage in the range indicated isobtained.

Illustrative of the adjuvants which may be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like; a lubricant such as magnesiumstearate; a sweetening agent such as sucrose, lactose or saccharin; aflavoring agent such as peppermint, oil of wintergreen or cherry. Whenthe dosage unit form is a capsule, it may contain in addition tomaterials of the above type a liquid carrier such as a fatty oil.Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, metyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccurring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

The invention is illustrated by the following examples.

EXAMPLE 12-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicAcid, Hydrochloride, Hydrate (S,S,S).

A quantity of 0.0079 mole of the hydrochloride of2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, phenylmethyl ester (S,S,S) dissolved in 100 ml of tetrahydrofuranwas catalytically debenzylated with hydrogen and 0.5 g of 20% Pd/carbonat low pressure. The catalyst was filtered off and the product wasprecipitated as a relatively nonhydroscopic solid by the addition of a10 fold quantity of ether; wt 3.7 g (88%); mp 120°-140° C.; tlc (20%MeOH-CHCl₃ /SiO₂) one spot, Rf 0.5-0.7; [α]_(D) ²³ =+31.6° (1.05% EtOH).

Anal. Calc'd for C₂₇ H₃₄ N₂ O₇.HCl.H₂ O: C, 58.63; H, 6.74; N, 5.07;Found: C, 58.59; H, 6.38; N, 5.06.

The noncrystalline diester hydrochloride starting material used abovewas prepared by treatment of 5.54 g (0.0079 mole) of the maleate salt(prepared by the process of Example 5) with excess saturated sodiumbicarbonate, extraction of the free base into 50% ether-ethyl acetate,treatment of this solution with excess hydrogen chloride andconcentration at reduced pressure.

EXAMPLE 22-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicAcid, Hydrochloride, Hydrate, (S,S,S).

Procedure A: Debenzylation procedure.

2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl[amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, phenylmethyl ester, maleate, (S,S,S) (prepared by the procedure ofExample 6) was catalytically debenzylated by the procedure set forth inExample 1 to yield the product; mp 105°-120° C.; yield, 56%; tlc (20%MeOH-CHCl₃ /SiO₂) one spot Rf 0.5-0.6; [α]_(D) ²³ =+10.9° (1.03% EtOH).

Anal. Calc'd. for C₂₅ H₃₀ N₂ O₅.HCl.H₂ O: C, 60.90; H, 6.75; N, 5.68;Found: C, 61.00; H, 6.37; N, 5.59.

Procedure B: Via cleavage of 1,1-dimethylethyl ester.

A quantity of 100 g of trifluoroacetic acid was added to 11.6 g (0.023mole) of2-[2-[[1-ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, 1,1-dimethylethyl ester (S,S,S) (prepared by the procedure ofExample 7). The mixture was stirred for one hour at room temperature.Most of the trifluoroacetic acid was removed on the rotary evaporatorand the remaining traces were removed by the successive additions andremoval by rotary evaporation of 2×50 ml of THF. The residual oil wasdissolved in about 400 ml of dry ether and the hydrochloride wasprecipitated by addition of a solution of 1.0 g (excess) of dry hydrogenchloride dissolved in 20 ml of dry ether. After filtration and washingwith dry ether, the filter cake was dissolved in about 250 ml of water.This solution was filtered through celite and freeze-dried to obtain theproduct as a partial hydrate; 10.0 g (90%); mp 113°-120° C.

Anal. Calc'd. for C₂₅ H₃₀ N₂ O₅.HCl.3/4 H₂ O: C, 61.55; H, 6.70; N,5.74; Found: C, 61.51; H, 6.49; N, 5.70

EXAMPLE 32-[2-[(1-Carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicAcid, Hydrochloride, Hydrate (S,S,S).

A solution of 0.553 g (0.001 mole) of2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) (prepared by the process ofExample 1) in 4 ml (0.004 mole) of 1 N sodium hydroxide and 4 ml ofmethanol was allowed to stand at room temperature for 20 hours. Thereaction solution was added to 5 ml of 1 N hydrochloric acid andconcentrated at reduced pressure. The last amounts of water were removedby two successive additions and removal at reduced pressure of 25 mlportions of ethanol. The organic portion of the residue was dissolved in0.5 ml of methanol. Chloroform (30 ml) was added and the solution wasdried over sodium sulfate, charcoaled, filtered, and concentrated togive 0.45 g product. This amorphous material was dissolved in 20 ml oftetrahydrofuran and 100 ml of ether was added to precipitate a nearwhite solid product; wt 0.4 g; mp 145°-170° C.; yield, 80%; tlc (20%MeOH-CHCl₃ /SiO₂) Rf 0.1; [α]_(D) ²³ =+37.8° (1.09% MeOH).

Anal. Calc'd for C₂₅ H₃₀ N₂ O₇.HCl.H₂ O: C, 57.19; H, 6.34; N, 5.34;Found: C, 57.17; H, 6.10; N, 5.51.

EXAMPLE 42-[2-[(1-Carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicAcid, Hydrochloride, Hemihydrate (S,S,S).

2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) was treated by the procedure setforth in Example 3 to yield the product; mp 140°-170° C.; yield, 39%;[α]_(D) ²³ =+14.5° (1.08% MeOH).

Anal. Calc'd for C₂₃ H₂₆ N₂ O₅.HCl.1/2 H₂ O: C, 60.59; H, 5.97; N, 6.15;Cl, 7.77; Found: C, 60.68; H, 6.04; N, 5.89; Cl, 7.04.

EXAMPLE 52-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicAcid, Phenylmethyl Ester, Maleate (S,S,S).

A stirred solution of 5.0 g (0.0158 mole) of ethylα-[(1-carboxyethyl)amino]benzenebutanoate hydrochloride (S,S) (preparedby the process of Example 8) in 200 ml of methylene chloride was treatedsuccessively with 1.60 g (0.0158 mole) of triethylamine, 2.14 g (0.0158mole) of 1-hydroxybenzotriazole, 5.16 g (0.0158 mole) of1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid,phenylmethyl ester free base (S-form) (prepared by the process ofExample 9); and then with 3.26 g (0.0158 mole) ofdicyclohexylcarbodiimide in 10 ml of methylene dichloride.Dicyclohexylurea gradually separated. The mixture was allowed to standat room temperature overnight. Hexane (300 ml) was added and the ureawas filtered. The filtrate was washed with 250 ml of saturated sodiumbicarbonate, dried over sodium sulfate and concentrated to removesolvent. The viscous residue was triturated with 50 ml of ether andfiltered to remove insolubles. The filtrate was concentrated to give 9.2g (99%) of crude base.

Preparation of maleate salt: A solution of 9.0 g (0.015 mole) of theabove crude base in 50 ml of ethyl acetate was treated with a warm (40°C.) solution of 1.86 g (0.016 mole) of maleic acid in 50 ml of ethylacetate. White crystals separated; wt 7.2 g (65%); mp 139°-141° C.; tlcof base (generated with aq. sodium bicarbonate treatment of the salt andethyl acetate extraction) showed one spot, Rf 0.7 (EtOAc/SiO₂).Recrystallization from ethyl acetate gave pure material of the same mp;[α]_(D) ²³ =+3.4° (1.05% EtOH).

Anal. Calc'd for C₃₄ H₄₀ N₂ O₇.C₄ H₄ O₄ : C, 64.74; H, 6.29; N, 3.98;Found: C, 64.48; H, 6.30; N, 3.99.

EXAMPLE 62-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicAcid, Phenylmethyl Ester, Maleate (S,S,S).

Ethyl α-[(1-carboxyethyl)amino]benzenebutanoate hydrochloride (S,S)(prepared by the process of Example 8) was coupled with1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, phenylmethyl esterfree base (S-form) (prepared by the process of Example 10) by the sameprocedure used in Example 5; yield, 61%; mp 151°-153° C. (recrystallizedfrom ethyl acetate); tlc of base showed one spot, Rf 0.8 (EtOAc/SiO₂);[α]_(D) ²³ =-11.7° (1.0% MeOH).

Anal. Calc'd for C₃₂ H₃₆ N₂ O₅.C₄ H₄ O₄ : C, 67.07; H, 6.25; N, 4.35;Found: C, 66.58; H, 6.09; N, 4.25.

EXAMPLE 72-[2-[[1-Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicAcid, 1,1-Dimethylethyl Ester (S,S,S).

A mixture of 8.38 g (0.03 mole) of ethylα-[(1-carboxyethyl)amino]benzenebutanoate (free amino acid) (S,S)(prepared by the process of Example 8), 8.09 g (0.03 mole) of1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1,-dimethylethylester hydrochloride (S-form) (prepared by the process of Example 11),4.05 g (0.03 mole) of 1-hydroxybenzotriazole and 250 ml of THF wascooled in an ice bath to 3°-5° C. With stirring, 3.04 g (0.03 mole) oftriethylamine was added, then a solution of 6.92 g (0.0335 mole) ofdicyclohexylcarbodiimide in 30 ml of THF was dropped in slowly over 20minutes. The reaction mixture was stirred at 3°-5° C. for one hour. Theice bath was removed, and the reaction mixture stirred an additional 3hours. The separated mixture of triethylamine hydrochloride anddicyclohexylurea was removed by filtration and washed with THF. Thefiltrate was evaporated on the rotary evaporation to remove allvolatiles. The resulting gum was dissolved in about 300 ml of ethylacetate. After filtration through celite the ethyl acetate solution wasextracted 2 times with 100 ml of saturated sodium bicarbonate solution,once with 75 ml of 2 N citric acid solution, once with 100 ml ofsaturated sodium bicarbonate solution and once with 100 ml of saturatedsodium chloride solution. After drying with anhydrous MgSO₄ andfiltration, the ethyl acetate was removed on the rotary evaporator toyield 16.9 g of a light brown gum. This gum was dissolved in 350 ml ofboiling hexane and decanted through celite. The hexane solution wascooled in ice, seeded and stirred until crystallization was wellestablished. The product was filtered, washed with cold hexane anddried; wt 11.6 g (78%); mp 68.5°-71° C.; [α]_(D) 23=-12.2° (2% MeOH).Pure material had mp 71°-72° C.; [α]_(D) 23=-12.6° (2% MeOH). Themaleate salt had mp 127.5°-128.5° C.; [α]_(D) 23=+46.4 (2% MeOH).

EXAMPLE 8 Ethyl α-[(1-Carboxyethyl)amino]benzenebutanoate Hydrochloride(S,S).

A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl2-bromo-4-phenylbutanoate in 25 ml of dimethylformamide was treated with1.8 ml of triethylamine and the solution was heated at 70° C. for 18hours. The solvent was removed at reduced pressure and the residue wasmixed with water and extracted with ethyl ether. The organic layer waswashed with water and dried over magnesium sulfate. Concentration of thesolvent at reduced pressure gave the oily t-butyl ester of theintermediate which was found to be sufficiently pure by gas liquidchromatography for further use.

A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroaceticacid was stirred at room temperature for one hour. The solvent wasremoved at reduced pressure and the residue was dissolved in ethyl etherand again evaporated. This operation was repeated. Then the ethersolution was treated dropwise with a solution of hydrogen chloride gasin ethyl ether until precipitation ceased. The solid, collected byfiltration, was a mixture of diastereoisomers, mp 153°-165° C., [α]_(D)23=+3.6° (1% MeOH).

In order to separate the preferred, S, S isomer, a suspension of 10.0 gof the mixture in 200 ml of methylene chloride was stirred at roomtemperature for five minutes and filtered; the solid was washed withadditional methylene chloride and finally ether. The solid material, mp202°-208° C. (dec.), [α]_(D) 23=-29.3° (1% MeOH) was the less preferreddiastereoisomer having the R, S configuration (S referring to theportion derived from L-alanine). The preferred S, S diastereoisomer wasrecovered from the filtrate after concentration and trituration of theresidue with ether; mp 137°-139° C.; [α]_(D) 23=+31.3° (1% MeOH).

The free amino acid (S,S-form) was prepared by treatment of an aqueoussolution of the hydrochloride with saturated sodium acetate. The productwas filtered, washed efficiently with cold water and recrystallized fromethyl acetate; mp 149°-151° C.; [α]_(D) 23=+29.7°

(1% 0.1 N HCl). EXAMPLE 91,2,3,4-Tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic Acid,Phenylmethyl Ester, Hydrochloride (S-form).

A mixture of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride (S-form) and 600 ml of benzyl alcohol was saturatedwith hydrogen chloride gas. The temperature rose to 45° C. The mixturewas stirred at room temperature for three days. A relatively smallamount of solid was filtered off and the filtrate was treated with ca2-liters of ether to precipitate crude product; wt 37.5 g; yield, 83%.Purification was effected by treatment with excess saturated sodiumbicarbonate, extraction of base into ethyl acetate and precipitation ofhydrochloride salt with HCl gas. Recrystallization from methanol-ethergave pure product; mp 255°-260° C.; [α]_(D) 23=-81.3° (1.0% MeOH); tlc(20% MeOH-CHCl₃ SiO₂) one spot Rf 0.8.

Anal. Calc'd for C₁₉ H₂₁ NO₄.HCl: C, 62.72; H, 6.10; N, 3.85; Found: C,62.54; H, 5.99; N, 4.00.

EXAMPLE 10 1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic Acid,Phenylmethyl Ester, Hydrochloride (S-form).

Benzyl alcohol, 750 ml, was treated with 150 g of commercialpolyphosphoric acid and warmed and stirred at 90° C. to obtain ahomogeneous mixture. Solid 1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (S-form) 165.2 g was added. The mixture was stirred 4 hours at95°-105° C. and then allowed to stand at room temperature for 18 hours.A solution of 18.5 g gaseous hydrochloric acid in 2.5 l of anhydrousether was added, and the product separated slowly on cooling overnight.Filtration gave the crude benzyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride. This was purified by recrystallization fromethanol twice to give material with mp 190.5°-191° C.; [α]_(D) 23=-83.3°(1% 1:1 methanol/1 N hydrochloric acid).

EXAMPLE 11 1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic Acid,1,1-Dimethylethyl Ester Hydrochloride (S-form).

This compound was prepared by passing 447 g of isobutylene into a 0° C.solution of 63.5 g of 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid(S-form) in 650 ml of dry dioxane and 65 ml of concentrated sulfuricacid under nitrogen. The reaction vessel was sealed and shaken for 17hours at room temperature. The reaction vessel was vented and themixture was poured into 25 l of cold 2 N sodium hydroxide. The produceis extracted into ether. The ether solution was washed with water,dried, and concentrated to about 500 ml. This was treated with excess 6N isopropanolic hydrochloric acid to precipitate the product, which wascollected by filtration. A sample purified by recrystallization fromethanol/ether had mp 190°-192° C. (dec.), [α]_(D) 23=-88.7° (2% MeOH).

EXAMPLE 12

A quantity of 1000 tablets each containing 100 mg of2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) is produced from the followingingredients:

    ______________________________________                                        2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-                                    amino]-1-oxopropyl]1,2,3,4-Tetrahydro-6,7-                                    dimethoxy-3-isoquinolinecarboxylic acid,                                      hydrochloride hydrate (S,S,S)                                                                          100     g                                            Corn starch              50      g                                            Gelatin                  7.5     g                                            Avicel (microcrystalline cellulose)                                                                    25      g                                            Magnesium stearate       2.5     g                                            ______________________________________                                    

2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) and corn starch are admixed with anaqueous solution of the gelatin. The mixture is dried and ground to finepowder. The Avicel and then the magnesium stearate are admixed with thegranulation. This is then compressed in a tablet press to form 1000tablets each containing 100 mg of active ingredients.

EXAMPLE 13

A quantity of 1000 tablets each containing 200 mg of2-[2-[[1-ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) is produced from the followingingredients:

    ______________________________________                                        2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-                                    amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-                                   dimethoxy-3-isoquinolinecarboxylic acid,                                      hydrochloride, hydrate (S,S,S)                                                                            200 g                                             Lactose                     100 g                                             Avicel                      150 g                                             Corn starch                 50 g                                              Magnesium stearate          5 g                                               ______________________________________                                    

The2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) lactose and Avicel are admixed,then blended with the corn starch. Magnesium stearate is added. The drymixture is compressed in a tablet press to form 1000, 505 mg tabletseach containing 200 mg of active ingredient. The tablets are coated witha solution of Methocel E 15 (methyl cellulose) including as a color alake containing yellow No. 6.

EXAMPLE 14

Two piece No. 1 gelatin capsules each containing 250 mg of2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S) are filled with a mixture of thefollowing ingredients:

    ______________________________________                                        2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-                                    amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-                                   dimethoxy-3-isoquinolinecarboxylic acid,                                      hydrochloride, hydrate (S,S,S)                                                                           250 g                                              Magnesium stearate         7 g                                                USP lactose                193 mg                                             ______________________________________                                    

EXAMPLE 15

An injectable solution is produced as follows:

    ______________________________________                                        2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-                                    amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-                                   dimethoxy-3-isoquinolinecarboxylic acid,                                      hydrochloride, hydrate (S,S,S)                                                                            500 g                                             Methyl paraben              5 g                                               Propyl paraben              1 g                                               Sodium chloride             25 g                                              Water for injection q.s.    5 l                                               ______________________________________                                    

The active substance, preservatives and sodium chloride are dissolved in3 liters of water for injection and then the volume is brought up to 5liters. The solution is filtered through a sterile filter andaseptically filled into presterilized vials which are then closed withpresterilized rubber closures. Each vial contains 5 ml of solution in aconcentration of 100 mg of active ingredient per ml of solution forinjection.

We claim:
 1. A substituted acyl compound of1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid having the formula##STR5## where R is hydrogen, lower alkyl or phenylalkyl; R₁ ishydrogen, lower alkyl, or benzyl; R₂ is hydrogen, or lower alkyl and Aris phenyl, or substituted phenyl having 1 or 2 substituents selectedfrom the group consisting of fluorine, chlorine, bromine, lower alkyl,lower alkoxy, hydroxy or amino; X and Y are independently hydrogen,lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, hydroxy, or X and Y together are methylenedioxy; and m is0 to 3; wherein lower alkyl, alkyl in the group phenylalkyl; and loweralkoxy has 1 to 4 straight or branched carbon atoms and thepharmaceutically acceptable salts thereof.
 2. A substituted acylcompound of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid accordingto claim 1 having the formula ##STR6## where R is hydrogen, t-butyl, orbenzyl; R₁ is hydrogen or lower alkyl; R₂ is hydrogen, methyl or ethyl;X and Y are independently hydrogen, lower alkyl, hydroxy or loweralkoxy; and the pharmaceutically acceptable salts thereof.
 3. Asubstituted acyl compound of 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid according to claim 2 having the formula ##STR7## where R₂ ishydrogen, methyl or ethyl and the pharmaceutically acceptable saltsthereof.
 4. A substituted acyl compound of1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid according to claim 2having the formula ##STR8## where R₂ is hydrogen, methyl or ethyl andthe pharmaceutically acceptable salts thereof.
 5. The compound accordingto claim 2 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, phenylmethyl ester, maleate (S,S,S).
 6. The compound according toclaim 2 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxylicacid, phenylmethyl ester, maleate (S,S,S).
 7. The compound according toclaim 2 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, 1,1-dimethylethyl ester, (S,S,S).
 8. The compound according toclaim 3 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S).
 9. The compound according to claim3 which is2-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S).
 10. The compound according toclaim 4 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, hydrochloride, hydrate (S,S,S).
 11. The compound according toclaim 4 which is2-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, hydrochloride, hemihydrate (S,S,S).
 12. The compound according toclaim 3 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, hydrochloride, (S,S,S).
 13. The compound according toclaim 4 which is2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, hydrochloride (S,S,S).
 14. A pharmaceutical compositioncomprising 10 to 500 mg of a substituted acyl compound of a1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a mixture ofcompounds according to claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 15. A method oftreating hypertension by administering an effective amount of asubstituted acyl compound of 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid according to claim 1 or a pharmaceutically acceptable salt thereof.